The goal of this application is to establish a Clinical Center of TrialNet at the University of California at San Francisco (UCSF) Diabetes Center, with the ultimate long-term objective to develop therapies to prevent the onset of Type 1 diabetes mellitus (T1DM). UCSF is uniquely positioned to serve as a study site for this multicenter trial, given a strong established diabetes program, a large population base for subject recruitment, and an established track record with clinical research and autoimmune interventions for T1DM. Clinicians at the UCSF Diabetes Center now provide care for approximately 3400 patients, with 100 new patients with Type 1 diabetes each year. In addition, the center has investigators with extensive experience in both clinical and basic science research, and with NIH-funded Pediatric and General Clinical Research Centers. The investigators are well positioned to recruit subjects from within the UCSF system, and widely from a preexisting referral net throughout Northern California. The diversity of the population suggests that subjects will be recruited from a variety of ethnicities. This application will build on UCSF?s past role as an Affiliate in the Diabetes Prevention Trial-1 (DPT-1). Specifically, the study goals are: Specific Aim 1: To implement and continue the DPT-1 protocols. This includes creation of an infrastructure that will enhance follow-up of subjects already entered into the DPT-1, as well as recruitment to screen and stage new subjects, with subsequent enrollment of those at intermediate risk into the oral insulin study arm. Specific Aim 2: To participate in other trials developed through TrialNet. Specific Aim 3: To implement a novel protocol involving treatment of individuals at high risk for Type 1 diabetes with a non-FcR binding anti-CD3 monoclonal antibody (mAb) (hOKT3g1(Ala-Ala)). An ongoing Phase I/II trial of this agent in new onset T1DM has shown that administration of the drug is safe, and has suggested efficacy in preserving insulin secretory capacity over time. Our rationale for this application is that if similar effects are seen in patients in whom the earliest signs of beta cell dysfunction are detected, and then progression to diabetes might be prevented.